Malaria causes more mortality globally than any other parasitic disease, yet a full understanding of disease pathophysiology is lacking, and effective treatments for severe malaria are limited. Nitric oxide (NO) has antimicrobial effects in vitro against a wide variety of microorganisms including Plasmodium falciparum. Recently, we noted increased NO production and leukocyte NO synthase type 2 (NOS2) expression in Tanzanian children with asymptomatic malaria. However, NO production and NOS2 expression were markedly decreased in children with cerebral malaria. This proposal is designed to extend our earlier work to examine the molecular mechanism(s) responsible for the decreases in NO production and NOS2 expression in severe disease, and to determine if these findings are seen in adults in a region with different malaria epidemiology. We will clarify the role of NO and NOS2 as molecular markers in severe malaria and examine their potential roles in the pathogenesis of severe disease. Our aims are to (i) determine the mechanism for decreased systemic NO production and NOS2 expression in severe malaria; (2) determine if there are certain NOS2 and cytokine gene allelic markers associated with severe malaria, and (3) establish whether NO is also an inverse molecular correlate of malaria severity in other age groups (adults vs children) and in regions with different malaria epidemiology (Indonesia vs Tanzania). Accomplishing these goals will add greatly to our overall understanding of the pathogenesis of severe malaria. Furthermore, this work may result in novel strategies for the treatment and prevention of severe malaria.